Haemophilus influenzae is a small, non-motile, Gram-negative coccobacillus. It is a respiratory pathogen that causes a wide spectrum of human infections, including: asymptomatic colonization of the upper respiratory tract (i.e. carriage); infections that extend from colonized mucosal surfaces to cause otitis media (inflammation of the middle ear), bronchitis, conjunctivitis, sinusitis, urinary tract infections and pneumonia; and invasive infections, such as bacteremia, septic arthritis, epiglottis, pneumonia, empyema, pericarditis, cellulitis, osteomyelitis and meningitis. H. influenzae was the first bacterium for which a complete genome sequence was published [1].
H. influenzae strains are either capsulated (typeable) or non-capsulated (non-typeable), and there are six major serological types of capsulated strains (a to f). 95% of H. influenzae-caused invasive diseases are caused by H. influenzae type b (‘Hib’) strains. The most serious manifestation of Hib disease is meningitis, but the introduction in the 1980s of vaccines based on conjugated Hib capsular saccharides has hugely reduced incidence of this disease.
Although Hib infections can now be controlled by vaccination, other pathogenic H. influenzae strains remain a risk. For instance, non-typeable H. influenzae (NTHi) is responsible for otitis media (OM), particularly chronic OM. While OM is rarely associated with mortality, it is associated with significant morbidity. Hearing loss is the most common complication of OM, with behavioral, educational and language development delays being additional consequences of early onset OM with effusion. Acute OM is the most common bacterial infection in children in the USA. The non-typeable H. influenzae biogroup aegyptius causes epidemic conjunctivitis and Brazilian purpuric fever (BPF) [2], with BPF having a mortality of up to 70%.
To date, antibiotics are the main tool against the spectrum of clinical entities known collectively as OM, but widespread use of antibiotics for OM has met with controversy due to the emergence of multiple-antibiotic resistant microorganisms. Progress towards a vaccine is slow due to an incomplete understanding of both the pathogenesis of OM and the immune response to it.
The genome sequence of the serotype d strain KW20 [1,3] has been useful for understanding basic H. influenzae biology, but it has not been so useful in countering pathogenic H. influenzae strains, as serotype d strains are generally not pathogens.
It is an object of the invention to provide polypeptides for use in the development of vaccines for preventing and/or treating infections caused by non-typeable H. influenzae strains. In particular, it is an object to provide polypeptides for use in improved vaccines for preventing and/or treating otitis media. The polypeptides may also be useful for diagnostic purposes, and as targets for antibiotics.